Abstract
The JO25567 study was a randomized phase II study to investigate the efficacy of the combination therapy consisted with erlotinib and bevacizumab for non-squamous nonsmall-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation (1). The study showed that the progression-free survival (PFS) of the combination therapy group was longer than that of the erlotinib monotherapy group. The median PFS were 16.0 months (95% CI, 13.9-18.1) vs. 9.7 months (95% CI, 5.7-11.1) respectively. The over-all survival (OS) data are immature, but this study suggested a remarkable efficacy of this combination chemotherapy. Angiogenesis is essential for tumor growth, and a high microvessel density has been identified as a worse prognostic and a predictive factor of metastasis. Vascular endothelial growth factor (VEGF) was identified as the most potent and specific angiogenic mitogen for endothelial cells. VEGF expression is regulated by many cytokines and growth factors, for example interleukin-1, interleukin-6, transforming growth factor (TGF), and basic fibroblast growth factor, and so on. EGFR is expressed on vascular endothelial cells, which induce tube formation in response to EGF or TGF-alpha. Signaling through the EGFR axis also plays a role in the regulation of angiogenesis. At the cellular level, activation of EGFR by its ligands such as EGF or TGF-alpha results in increased VEGF expression (2). EGFR-tyrosine kinase inhibitors (EGFRTKIs) inhibit tumor cell growth and blocks synthesis of angiogenic proteins by tumor cells, like VEGF and, TGFalpha. In addition, VEGF production is upregulated by hypoxia via hypoxia-inducible factors (HIFs) in HIH3T3 cells transfected with mutant EGFR constructs. Hypoxia which is common in solid tumors then turns on the signal to initiate angiogenesis. Although the mechanism has not been clearly elucidated, it is suggested that EGFR is associated with enhanced signaling by phosphatidylinositol 3-kinase, which synergizes with hypoxia to regulate VEGF (3). Also, a recent study demonstrated a novel molecular pathway in which hypoxia promotes tumor growth by transcriptional activation of the Met proto oncogene. Through these some pathways, VEGF was regulated in tumors. With regard to prognosis, the role of angiogenesis has been established in the progression of lung cancers. Results from a retrospective study in Japan showed that the serum concentrations of EGF, hepatocyte growth factor (HGF), and VEGF in patients with NSCLC who received EGFR-TKI were significantly higher among patients with progressive disease (PD) than among those with stable disease (SD) or partial response (PR) (4). Increasing HGF and VEGF concentrations were significantly associated with lesser tumor shrinkage, independent of the EGFR mutation status. Furthermore, the higher concentrations of HGF and VEGF were significantly associated with shorter PFS and OS. The study suggested that the serum concentration of VEGF might be an independent prognostic factor in NSCLC. Excessive angiogenesis is also associated with resistance to EGFR-TKI. First-line treatment with an EGFR-TKI of
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